1. Field of the Invention
The present invention relates generally to a class of compounds derived from naphthalene, such as apogossypol and derivatives thereof, for treating a variety of disorders, diseases and pathologic conditions, and more specifically, for treating cancer, autoimmune diseases, and/or inflammation.
2. Background Information
The apoptotic cascade in cells is known to lead to cell death. When anti-apoptotic proteins, such as BCL-2 family proteins, are overproduced by the cells, uncontrollable cell growth may ensue, potentially leading to the development of various serious diseases, disorders, and pathologies, particularly cancer.
Apoptosis plays a role in tissue homeostatis, for the physiological removal of unwanted cells during development and in host defense mechanism. The BCL-2 family of proteins are believed to be involved in regulating of apoptosis. Specifically, members of the BCL-2 gene family can act to inhibit programmed cell death (e.g., BCL-2, BCL-XL, ced-9) or promote cell death (e.g., Bax, Bak, BCL-XS). Pro-survival members of this family, such as BCL-XL, contain, on the surface, a hydrophobic groove in which is believed to allow binding of the BH3 domain of the pro-apoptotic counterpart. This binding is believed to play role in apoptosis regulation, in fact pro- and anti-survival proteins can reverse each other function through dimerization.
Therefore, a need exists to inhibit anti-apoptotic proteins, such as the BCL-2 family proteins. Various potential BCL-2 antagonists have been previously identified. However, none of these compounds inhibits all six proteins in the BCL-2 family, i.e., all of the following proteins: BCL-XL, BCL-2, BCL-W, BCL-B, BFL-1, and MCL-1. For example, none of the previously identified synthetic BCL-2 antagonists was effective at inhibiting the protein BFL-1. Therefore, the efficiency of such antagonists is not as high as desired. In addition, the existing antagonists are characterized by other drawbacks, such as insufficiency or safety issues.
As stated above, apoptosis is known to play a role in normal tissue homeostasis, thus ensuring a proper balance of cell production and cell loss. Defects in the regulation of programmed cell death may promote tumorgenesis, and also contribute to chemoresistance. Over-expression of anti-apoptotic BCL-2 family proteins occurs in many human cancers and leukemias, and therefore these proteins may be used as targets for the development of novel anticancer agents. Structural studies have elucidated a hydrophobic crevice on the surface of anti-apoptotic BCL-2 family proteins that binds the BH3 dimerization domain of pro-apoptotic family members. Thus, molecules that mimic the BH3 domain of pro-apoptotic proteins induce apoptosis and/or abrogate the ability of anti-apoptotic BCL-2 proteins to inhibit cancer cell death.
It has been previously shown that the natural product gossypol shown on FIG. 1A is an inhibitor of BCL-2, BCL-XL and MCL-1, functioning as a BH3 mimic. (−) Gossypol is currently in clinical trails, displaying single-agent antitumor activity in patients with advanced malignancies. Given that gossypol has toxicity problems likely due to two reactive aldehyde groups, we apogossypol (FIG. 1A), a compound that lacks these aldehydes, but retains activity against anti-apoptotic BCL-2 family proteins in vitro and in cells has been also evaluated previously. Recently, the efficacy and toxicity in mice of gossypol and apogossypol were compared. Preclinical in vivo data show that apogossypol has better efficacy and reduced toxicity compared to gossypol, as well as better single-dose pharmacokinetic characteristics, including, superior blood concentrations over time compared to gossypol, due to slower clearance. These observations indicate that apogossypol is a promising lead compound for cancer therapy.
BCL-2 family members are also believed to be involved in inflammatory disorders. For example, BCL-2 family members have been shown to play roles in neutrophil apoptosis and inflammatory accumulation. In several inflammatory diseases, the delay of neutrophil apoptosis is associated with reduced levels of the pro-apoptotic BCL-2 family member BAX. It has been also shown that eosinophils isolated from children with acute asthma had an increased expression of the anti-apoptotic protein BCL-2, which was inversely correlated with expiratory flow rate. BCL-2 family proteins are also associated with Crohn's disease. BAX expression is attenuated and BCL-XL expression is increased in T cells isolated from the lamina propria from patients with Crohn's disease. This shows that inflammatory cell survival, by means of prosurvival and anti-apoptotic signaling mechanisms, are involved in the pathogenesis of inflammatory diseases. Lupus is a complex systemic autoimmune disease, characterized by high levels of anti-DNA and anti-glomerular autoantibodies, activated B and T-cells, and glomerulonephritis. Neutrophils from lupus-susceptible mice display reduced rates of apoptosis. The decreased apoptosis is associated with the altered expression of BCL-2 family proteins contributing to the greater accumulation of neutrophils in the lupus-susceptible mice. Signaling studies using several different lupus strains indicate that multiple signaling pathways are upregulated in lymphocytes and non lymphocytes as disease evolves, including the activation of BCL-2 and BCL-XL. These anti-apoptotic molecules are known to prolong the lifespan of all cells, including autoreactive B and T cells.
In view of the above drawbacks and deficiencies of existing BCL-2 inhibitors, new antagonists of anti-apoptotic proteins, such as BCL-2 family proteins, are desired. It is desirable that such new antagonists be safer and more effective than the existing compounds. Some of such compounds have been now identified (see FIG. 1 B)